The present invention relates generally to biologically active ansa ring compounds and more specifically to biologically active atropisomeric forms of such compounds, to methods for their preparation, to pharmaceutical compositions including such compounds, and to therapeutic methods involving their administration.
Antibiotic or otherwise biologically active ansa ring compounds containing an aliphatic chain "bridge" connecting two nonadjacent positions of an aromatic nucleus are commonly referred to as ansamycins. [See, generally, Rinehart, Accounts Chem, Res., 5, 57(1972)]. Thus far, five generally representative groups within the general class of ansamycins have been identified:
1. Rifamycins, produced from Streptomyces mediterranei [Sensi, et al., Farmaco Ed. Sci., 14, 146 (1959)];
2. Streptovanicins, produced from Streptomyces spectabilis [Siminoff, et al., Am. Rev. Tuberc. Pulm. Dis., 75, 576 (1957)];
3. Tolypomycins, produced from Streptomyces tolypophorus [Kishi, et al., Tetrahedron Lett., 91 (1969); Shibata, et al., J. Antibiot., 24, 810 (1971)];
4. Geldanamycin, produced from Streptomyces hygroscopicus var. geldanus var. nova [DeBoer, et al., J. Antibiot., 23, 442 (1970)]; and,
5. Maytansine, produced from Maytenus ovatus [See, e.g., Kupchan, et al., J.A.C.S., 94, 1354 (1972)]U.S.
Various derivatives of such ansamycin compounds have been prepared by processes which leave the aliphatic bridge intact (e.g., streptovaricin acylates as described in U. S. patent application Ser. No. 328,727). For the purposes of the present invention, the term "ansa ring compound" shall mean any naturally occurring or synthetically derived ansamycin compound containing an intact aliphatic bridge as above described.
Each ansa ring compound characteristically displays a stereochemical property of "helicity" in much the same manner as complex nucleic acids and certain proteins, i.e., each is wound in a helical or screw-like manner-- either in the manner of a right handed threaded screw (hereafter, "P-helicity") or of a left handed threaded screw (hereafter, "M-helicity").
Atropisomerism is generally defined as any type of stereoisomerism due to restricted rotation about single bonds. [See, e.g., Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill (1962)]. With respect to ansa ring compounds, the atropisomeric forms would exhibit P-helicity or M-helicity opposite that ordinarily exhibited by the compounds.